A Food-Effect Study to Evaluate the Oral Bioavailability of Desidustat.

This randomized, single-treatment, 2-sequence study evaluated the food effect on oral bioavailability of desidustat. Healthy adult male and female subjects were enrolled and randomly assigned to receive desidustat 50 mg orally in a fasting state in one period and a fed state in the other period. A standardized high-fat, high-calorie breakfast was served to assess the food effect. The pharmacokinetic results showed that the time to maximum blood concentration of desidustat was delayed significantly (P < .0001) in the fed state compared to the fasting state. The ingestion of food decreased the maximum blood concentration (Cmax ) compared to the fasting state (mean Cmax , 3248 ng/mL in the fed state vs 5496 ng/mL in the fasting state). The geometric mean ratio of fed/fasting for log-normal (ln) Cmax was 57. The exposure decreased in the fed state compared to the fasting state (mean area under the concentration-time curve [AUC] over the dosing interval, 25 559 ng â€¢ h/mL in the fed state versus 33 705 ng â€¢ h/mL in the fasting state; mean AUC from time 0 to infinity [AUC0-∞ ], 25,910 ng â€¢ h/mL in the fed state vs 34 233 ng â€¢ h/mL in the fasting state). The geometric mean ratio of fed/fasting for lnAUC from time 0 to the last quantifiable concentration and ln AUC0- ∞  was 77 and 76, respectively. The 90%CI of fed/fasting ratio of the geometric mean of lnCmax , AUC over the dosing interval, and AUC0-∞ of desidustat 50 mg did not fall within 80%-125% margin. Therefore, the absence of food effect could not be established. It can be inferred that food has a significant effect on the oral absorption of desidustat. Therefore, food must not be consumed 1 hour before and 2 hours after the oral administration of desidustat.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral NLRP3 Inflammasome Inhibitor ZYIL1: First-in-Human Phase 1 Studies (Single Ascending Dose and Multiple Ascending Dose).

ZYIL1 is a nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome inhibitor, which prevents NLRP3-induced apoptosis-associated speck-like protein containing a caspase activation and recruitment domain oligomerization, thus inhibiting NLRP3 inflammasome pathway. We investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ZYIL1 after single and multiple doses in healthy subjects. The subjects aged 18-55 years were enrolled in 2 different studies: single and multiple ascending dose. Blood/urine samples were collected at designated time points for pharmacokinetic and pharmacodynamic analysis. In the single-ascending-dose study, 30 subjects were enrolled (6 subjects each in 5 dose groups). One adverse event was reported during the study. ZYIL1 was well absorbed with median time to maximum plasma concentration at 1-1.5 hours. The exposures were dose proportional across the dose ranges. ZYIL1 is excreted as an unchanged form via the renal route. The mean elimination half-life was 6-7 hours. In the multiple-ascending-dose study, 18 subjects were enrolled (6 subjects each in 3 dose groups). Eleven adverse events were reported by 6 subjects during the study. The accumulation index at steady state for area under the plasma concentration-time curve indicated that ZYIL1 has a marginal accumulation upon repeated dosing. Dose-proportional exposure was observed across the dose ranges. All subjects showed >90% interleukin (IL)-1ß inhibition in all dose groups for both studies. Inhibition in IL-1ß and IL-18 was observed throughout the 14 days of treatment in the multiple-dose study. The safety profile, rapid absorption, marginal accumulation, and significant inhibition of IL-1ß and IL-18 level support its development for the management of inflammatory disorders.

Heart Rate Variability Biofeedback Improves Emotional and Physical Health and Performance: A Systematic Review and Meta Analysis.

We performed a systematic and meta analytic review of heart rate variability biofeedback (HRVB) for various symptoms and human functioning. We analyzed all problems addressed by HRVB and all outcome measures in all studies, whether or not relevant to the studied population, among randomly controlled studies. Targets included various biological and psychological problems and issues with athletic, cognitive, and artistic performance. Our initial review yielded 1868 papers, from which 58 met inclusion criteria. A significant small to moderate effect size was found favoring HRVB, which does not differ from that of other effective treatments. With a small number of studies for each, HRVB has the largest effect sizes for anxiety, depression, anger and athletic/artistic performance and the smallest effect sizes on PTSD, sleep and quality of life. We found no significant differences for number of treatment sessions or weeks between pretest and post-test, whether the outcome measure was targeted to the population, or year of publication. Effect sizes are larger in comparison to inactive than active control conditions although significant for both. HRVB improves symptoms and functioning in many areas, both in the normal and pathological ranges. It appears useful as a complementary treatment. Further research is needed to confirm its efficacy for particular applications.

Mind-body treatments of irritable bowel syndrome symptoms: An updated meta-analysis.

Irritable bowel syndrome (IBS) is a widespread chronic functional gastrointestinal (GI) disorder having bidirectional comorbidity with psychiatric disorders. This review focuses on psychological treatment of IBS, focusing on symptom severity rather than IBS diagnostic criteria. We chose this dimensional approach in order to assess mind-body effects as an alternative or complement to conventional medical treatment, which focuses on symptom relief. We calculated the effect sizes for various psychosocial-mind-body therapies (MBTs) for IBS symptoms in both children and adults. Therapies included meditation, relaxation, yoga, autogenic training, progressive relaxation, general training in stress coping, hypnotherapy, biofeedback, psycho-education, psychodynamic psychotherapy, and cognitive behavioral therapy. We performed a meta-regression analyses and mixed effects contrasts to find various outcome differences, and we analyzed their relative efficacy in both children and adults. We found 53 studies in 50 reports describing randomized controlled trials. Medium to high effect sizes were found across all methods compared with various controls, with possibly higher effects for children. We found no systematic differences among treatment methods. Meta-regression analyses showed no significant effect for the presence of psychophysiological training, meditation or explicit exposure procedures as treatment components, although most MBTs include exposure as a nonexplicit treatment characteristic, and many relaxation techniques have meditative characteristics. We conclude that there is considerable evidence that an array of mind-body and other psychological therapies can be effective complements to medical treatment for IBS symptom severity, with little evidence for relative superiority of any particular approach. We suggest that the various methods may operate through different mechanisms.